This invention relates to a method for the topical delivery of active agents (e.g., drugs), and compositions used therein. More specifically, this invention relates to a method for enhancing the transmembrane penetration of benefit agents using a certain non-ionic lipid/surfactant-containing formulation as an enhancing agent, and the compositions used therein.
The topical delivery of an active agent, such as a drug, from a given vehicle is a multistep process which involves; 1) the dissolution, diffusion and/or release of the agent from the vehicle; 2) the transport of the agent to the absorption site; 3) the permeation of the agent through the limiting barrier at the target site; and eventually 4) the elimination of the agent via blood circulation. In order for an active agent to be effectively transported into the epidermal absorption site, the agent must be present at the skin/vehicle interface, be soluble in the available surrounding fluids, and be capable of diffusing down the hair follicle or partitioning into the stratum corneum.
It is well known in the art that the skin presents a formidable barrier to the penetration of active agents due to the presence of the stratum comeum, which is the outermost layer of the skin composed of close packed dead keratinized cells. Thus, the ability of a substance, which is applied to the skin surface, to penetrate through the skin is inversely related to the thickness of the stratum corneum layer.
One known method for enabling the penetration of active agents through the skin is via topical administration. One shortcoming associated with this method is that some active agents, in particular those having a relatively high molecular weight, are not easily absorbed by the skin.
Many methods for enhancing the local penetration of pharmacologically active agents are known in the art. In one approach, surface active agents are included in the pharmacologically active agent-containing formulation. However, this addition of surface active agents results in only a slight to moderate enhancement of permeability at the expense of damaging the barrier skin tissue. See, e.g, Zatz, J. L., Modification of Skin Permeation by Surface-Active Agents in Skin Permeation Fundamentals and Application, 149-162 (1993); and Barry, B. W., xe2x80x9cProperties That Influence Percutaneous Absorption in Dernatological Formulations,xe2x80x9d Percutaneous Absorption, 127-233 (1983). (Addition of xe2x80x9cpenetration enhancersxe2x80x9d increases the permeability of the stratum comeum by disrupting the lipid organization therein.)
Traditionally, the prime pathway for the topical delivery of active agents across the skin was thought to be through intercellular routes and transcellular routes of the stratum corneum. However, alternative means such as via appenageal transport, i.e., follicular transport, is gaining more acceptance in the scientific community. See, e.g., Schaefer, H., et al. Follicular Penetration in Prediction of Percutaneous Penetration: Methods, Measurements, and Modeling, 163-173 (1990)(optimum size for uptake of micro-beads by the skin appendages is between 5-7 xcexcm). Due to the comparatively lower barrier resistance of the follicles, follicular transport has particular relevance for enabling the delivery of active agents having low diffusion constants, varying solubility characteristics, and/or varying size characteristics.
One of the diseases associated with the hair follicle is androgenetic alopecia (xe2x80x9cAGAxe2x80x9d), which is the most common cause of hair loss in both men and women and is identifiable by the loss of hair over the vertex of the scalp. Commonly known treatments for AGA include hair follicle transplants, topical therapies, and orally prescribed anti-androgens. See, e.g., J. L. Roberts, xe2x80x9cAndrogenetic Alopecia in Men and Women: An Overview of Cause and Treatment,xe2x80x9d 9(6) Dermatology Nursing 379-386 (1997).
Minoxidil is a drug that is often prescribed for the treatment of AGA. Disadvantageously, clinical trials have shown that the topical application of a 2% minoxidil solution to patients experiencing hair loss results stimulated dense hair regrowth in only less than about 5% of the patients and moderate hair regrowth in only about 30% of the patients. See e.g., E. A. Olsen, et al., xe2x80x9cTopical Minoxidil in Early Male Pattem Baldness,xe2x80x9d 13, J. Amer. Acad. Derm. 185-192 (1985); and J. Roberts, xe2x80x9cAndrogenetic Alopecia: Treatment With Topical Minoxidil,xe2x80x9d 16(3) J. Amer. Acad. Derm. 705-710 (1987). Moreover, treatments with topical solutions of minoxidil require multiple daily applications, which is not only inconvenient but also expensive.
One known method for the topical administration of minoxidil is via a mousse formulation containing a cellulose derivative film former as disclosed in PCT Patent Application WO 88/01863. Disadvantageously, such cellulose derivatives hinder the diffusion of the minoxidil from the vehicle, which thereby leads to decreased efficacy of the minoxidil.
Various delivery systems are also known in the art for topically delivering anti-acne agents, anti-aging agents, and depigmentation agents to the epidermis and/or dermis. In one method, high levels of alcohol are used to faciliate the delivery of the agent. However, such alcohols disadvantageously tend to extract lipids from the skin surface, which leads to excessively dry skin and irritation. See, e.g. Zatz, J. L. Modification of Skin Permeation by Solvents in Skin Permeation Fundamentals and Application, 146-148 (1993).
It is therefore an object of this invention to provide improved compositions for enabling the topical delivery of pharmacologically active substances without significant adverse side effects on the skin or body membranes. It is also a further object to provide improved compositions for enabling the topical delivery of difficult-to-absorb agents for localized action. It is a further objective to provide an economic, effective topical treatment for hair loss that is convenient to apply. It is yet a further objective to provide improved compositions for enabling the topical delivery of anti-dandruff, depilatory, anti-acne, anti-aging, and depigmentation active agents into the skin.
In accordance with the present invention, we have found a composition for enhancing the topical delivery of benefit agents comprising, consisting essentially of, or consisting of, based upon the total weight of the composition,:
A. from about 1 percent to about 10 percent of a nonionic lipid selected from
i. glyceryl monoesters having a fatty acid chain containing from about 3 to about 50 carbon atoms;
ii. glyceryl diesters having a fatty acid chain containing from about 5 carbon atoms to about 25 carbon atoms;
iii. alkoxylated alcohols alkoxylated with ethylene oxide or propylene oxide;
iv. alkoxylated alkyl phenols alkoxylated with ethylene oxide or propylene oxide;
v. alkoxylated acids alkoxylated with ethylene oxide or propylene oxide;
vi. alkoxylated amides alkoxyiated with ethylene oxide or propylene oxide;
vii. alkoxylated sugar derivatives alkoxylated with ethylene oxide or propylene oxide;
viii. alkoxylated derivatives of natural oils or waxes alkoxylated with ethylene oxide or propylene oxide;
ix. polyoxyethylene polyoxypropylene block copolymers alkoxylated with ethylene oxide or propylene oxide;
x. polyoxyethylene fatty ethers having a fatty acid chain containing from about 10 carbon atoms to about 18 carbon atoms;
xi. steroids;
xii. fatty acid esters of alcohols where the fatty acid is straight or branched chain having from about 10 carbon atoms to about 20 carbon atoms and the alcohol is straight or branched chain having 1 to 10 carbon atoms; or
xiii. mixtures thereof;
B. from about 75 percent to about 98 percent of a vehicle solution comprised of:
1) a first vehicle component comprised of water or a mixture of water and a hydrophilic compound; and
2) a second vehicle component comprised of an alcohol, a polyol, or mixtures thereof; and
C. an effective amount of the benefit agent(s).
In another embodiment of the present invention, we have found a topical delivery system for active agents comprising, consisting of, or consisting essentially of, based upon the total weight of the delivery system,
A. from about 0.5 percent to about 10 percent, and preferably from about 0.5 percent to about 5 percent, of a nonionic lipid selected from
i. glyceryl monoesters having a fatty acid chain containing from about 3 to about 50 carbon atoms;
ii. glyceryl diesters having a fatty acid chain containing from about 5 carbon atoms to about 25 carbon atoms;
iii. alkoxylated alcohols alkoxylated with ethylene oxide or propylene oxide;
iv. alkoxylated alkyl phenols alkoxylated with ethylene oxide or propylene oxide;
v. alkoxylated acids alkoxylated with ethylene oxide or propylene oxide;
vi. alkoxylated amides alkoxylated with ethylene oxide or propylene oxide;
vii. alkoxylated sugar derivatives alkoxylated with ethylene oxide or propylene oxide;
viii. alkoxylated derivatives of natural oils or waxes alkoxylated with ethylene oxide or propylene oxide;
ix. polyoxyethylene polyoxypropylene block copolymers alkoxylated with ethylene oxide or propylene oxide;
x. polyoxyethylene fatty ethers having a fatty acid chain containing from about 10 carbon atoms to about 18 carbon atoms;
xi. steroids;
xii. fatty acid esters of alcohols where the fatty acid is straight or branched chain having from about 10 carbon atoms to about 20 carbon atoms and the alcohol is straight or branched chain having 1 to 10 carbon atoms; or
xiii. mixtures thereof; and
B. from about 74 percent to about 99.5 percent of a vehicle solution comprised of:
1) a first vehicle component comprised of water or a mixture of water and a hydrophilic compound; and
2) a second vehicle component comprised of an alcohol, a polyol, or mixtures thereof.
In another embodiment of the present invention, we have found a method for enhancing the topical delivery of benefit agents which comprises, consists of, or consists essentially of topically administering to a human or animal the above-described composition. In yet another embodiment of the present invention we have found a method for treating hair loss comprising, consisting of, and/or consisting essentially of topically applying to skin at a desired area for hair induction the above-described composition, wherein the benefit agent is a hair loss treatment agent. In yet another embodiment of the present invention we have found a method for treating the effects of aging comprising, consisting of, and/or consisting essentially of topically applying to skin at a desired area a composition similar to that described with hair growth, but wherein the benefit agent is an anti-aging active agent. In yet another embodiment of the present invention we have found a method for treating acne comprising, consisting of, and/or consisting essentially of topically applying to skin at a desired area for treatment a composition similar to that described with respect to anti-aging, but wherein the benefit agent is an anti-acne active agent. In yet another embodiment of the present invention we have found a method for inducing hair loss comprising, consisting of, and/or consisting essentially of topically applying to skin at a desired area for treatment a composition similar to that described with respect to anti-aging, but wherein the benefit agent is a hair loss inducing active agent. In yet another embodiment of the present invention we have found a method for depigmenting the skin comprising, consisting of, and/or consisting essentially of topically applying to skin at a desired area for treatment a composition similar to that described with respect to anti-aging, but wherein the benefit agent is a depigmentation active agent.
The composition and methods of this invention provide a unique, convenient means for topically delivering benefit agents with minimal skin irritation, and when the active substance is minoxidil or mixtures thereof, the composition and methods of this invention provide an effective, economical method for treating hair loss resulting from alopecia. In addition, when the composition contains an effective amount of anti-acne agent, the composition and methods of this invention provide an effective, economic means for treating acne. Similarly, when the composition contains an effective amount of an anti-dandruff agent, a depilatory agent, an anti-aging agent or a depigmentation agent, the composition and methods of this invention provide an effective, economic means for treating the symptoms of dandruff, removing hair, preventing the signs of aging and depigmenting the skin, respectively.
Other features and advantages of the present invention will be apparent from the detailed description of the invention and from the claims.